Mental illness is a group of neurological disease mainly manifested in behavior and mental activity disorder, clinically manifested in abnormal mental activity, specifically manifested in disorders in varying degrees in perception, thinking, attention, memory, emotion, behavior, intelligence and consciousness.
Due to the complexity of the central nervous system, conventional antipsychotics still have their limitations. For example, the clinical drugs for the treatment of major depressive disorder (MDD) and anxiety have slow onset of action and poor efficacy; existing antipsychotic drugs are mostly ineffective in improving the negative symptoms and cognitive impairment in schizophrenia, and they are usually associated with side effects such as extrapyramidal reactions (EPS) and metabolic disorder. Therefore, there is a need to find new antipsychotics with high efficacy, low side effect, and broad treatment spectrum.
Dopamine system is involved in the regulation of many physiological functions such as movement, emotion, reward and cognition. Serotonin (5-HT) is also involved in the regulation of many physiological functions, such as body temperature regulation, emotional activities, pain, sleep-awakening. Therefore, the therapeutic effects of existing drugs for the treatment of central nervous system disease correlate closely to the regulation of neurotransmitters such as dopamine and 5-HT in the brain.
D2 receptor antagonists are developed as typical antipsychotics and they are also used in the treatment of insomnia; 5-HT2A receptor antagonism can reduce EPS, improve negative symptoms, cognitive impairment, depression, anxiety and insomnia (European Journal of Pharmacology, 2000, 407: 39-46). However, pure D2 antagonists or D2/5-HT2A antagonists still have side effects of varying degrees.
5-HT1A receptor agonists have showed good prospect for the clinical treatment of severe depression, anxiety, depression and improvement of negative symptoms and cognitive function in patients with schizophrenia (CNS Drugs, 2013 September, 27: 703-16). For example, 5-HT1A receptor agonist BAY-3702 showed neuroprotective, anxiolytic and antidepressant effects in animal models (European Journal of Pharmacology, 1998, 357: 1-8); gepirone can be used to alleviate specific primary depressive disorder (U.S. Pat. No. 4,771,053), such as severe depression, endogenous depression and atypical depression; buspirone can be used to treat various symptoms associated with attention deficit and hyperactivity disorder (ADHD). D2 receptor agonist in combination with 5-HT1A receptor agonist can be effective in the treatment of ADHD and Parkinson's disease (WO200016777A); ixabepilone can be effective in the treatment of cognitive impairment associated with Alzheimer's disease or Parkinson's disease by improving memory (U.S. Pat. No. 5,824,680).
Dopamine receptor partial agonists can improve the positive symptoms, negative symptoms, depression, anxiety and cognitive deficits associated with schizophrenia while rarely cause increased serum prolactin level as D2 receptor antagonists, rarely cause weight gain and metabolic disorders as D2/5-HT2A receptor antagonists. Generally, they are safety and well tolerated.
Thus, a drug has multiple pharmacological effects on DA/5-HT receptors is conducive to better regulation of DA/5-HT system in the brain so as to treat central nervous system diseases. The present invention provides a novel class of compounds endowed with D2/5-HT1A/5-HT2A multireceptor activities that are effective for the treatment of central nervous system disorders, particularly depression, manic-depression, schizophrenia, anxiety, phobias, autism, Alzheimer's disease, bipolar disorder, hysteria, obsessive-compulsive disorder, hyperkinetic syndrome and the like.